Inflammatory Biomarkers, Hematopoietic Stem Cells, and Symptoms in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy

Abstract

Background: Fatigue and insomnia are common symptoms experienced by breast cancer patients undergoing adjuvant radiation therapy (RT), yet the underlying mechanisms of these symptoms are unclear. In particular, the roles of hematopoietic stem cells (HSCs) and inflammatory cytokines remain to be elucidated.

Methods: Breast cancer patients (n = 147) completed questionnaires to longitudinally assess symptoms before, during, and after adjuvant RT. Phlebotomies were performed prior to RT, at the second and fifth treatment fractions, end of treatment (EOT), and 1 month after completing RT, assessing for CD34⁺, CD45⁺, full hematology, and 17 inflammatory cytokines. The associations between symptoms and all biomarkers were evaluated. All statistical tests were 2-sided.

Results: General fatigue and insomnia worsened with RT, with peak levels observed at EOT, which remained statistically significant even after controlling for anxiety and depression (P < .05 for all). CD34⁺, CD45⁺, white blood cell, and lymphocyte counts decreased, with the lowest levels also observed at EOT (P < .001). Fatigue and insomnia were associated with changes in both interferon γ-induced protein 10 (IP-10) - (P = .03 and P = .01, respectively) and tumor necrosis factor receptor II (TNF-RII) (P = .02 and P = .006, respectively), while mental fatigue was associated with increased matrix metalloproteinases-2 (MMP-2) levels (P = .03). Patients who received prior chemotherapy demonstrated statistically significantly greater severity in all symptoms, with lower baseline HSC levels.

Conclusions: This is the first longitudinal study to examine linkages between symptoms, HSCs, and cytokines, demonstrating that fatigue and insomnia shared associations with increasing serum levels of IP-10 and TNF-RII, and mental fatigue was associated with increasing serum levels of MMP-2. Our findings highlight opportunities for further research into mechanisms and potential interventions for these symptoms.

Figure 1.

Changes in symptoms and hematologic biomarkers. A) Symptom changes during and after radiation therapy (RT). Mean severity levels of component scores in general fatigue; insomnia; anxiety; and depression, in patients during and 1-month post-RT. Time on the x-axis denotes first phlebotomy (D1, pretreatment), second (D2) and fifth treatment fraction (D5), and final day of RT (end of treatment [EOT]), and 1 month post-RT (1 M). All data are represented as mean of the absolute count for the entire cohort, for each time point. B) CD34+ (HSCs) and other biomarker changes during and after RT. Counts of WBCs, CD45+ cells, RBCs, platelets, lymphocytes, Hgb, and CD34+ cells are plotted as a function of RT alone or RT following adjuvant chemotherapy. Patients receiving chemotherapy had lower baseline levels of CD34+, CD45+, WBCs, and lymphocytes that were statistically significant compared to RT only, whereas the average baseline counts of RBCs, Hgb, and platelets were similar across the entire cohort. All data are presented as mean + SD. Hgb = hemoglobin; RBC = red blood cell; WBC = white blood cell.

Figure 2.

Associations among cytokines with general fatigue and mental fatigue. A) General fatigue is associated with TNF-RII and IP-10. Data from the entire cohort of patients (n = 147) demonstrated a positive correlation between TNF-RII (P = .02) and IP-10 (P = .03) with increasing general fatigue during the course of radiation therapy (RT). B) Association of mental fatigue with MMP-2 during the course of RT. MMP-2 is positively associated with mental fatigue during the course of RT for all 147 patients (P = .03). 1M = 1 month post-RT; D1 = pretreatment; D2 = second fraction; D5 = fifth fraction; EOT = end of treatment.

Figure 3.

The association of symptoms with inflammatory biomarkers. A) Different cytokines are associated with symptoms in RT following adjuvant chemotherapy. Statistically significant associations between cytokines and symptoms are indicated with black dots (P < .05); cytokines shared by general fatigue and insomnia are denoted with an asterisk (*). Red represents a positive correlation; green represents a negative correlation. B) A hypothetical model illustrating the possible mechanisms underlying the development of symptoms in BC patients undergoing adjuvant RT. Local RT induces the release of cytokines/chemokines such as IP-10, TNF-RII, and MMP-2 through a local inflammatory response. The released cytokines engage with transporters in the blood–brain barrier, affecting hypothalamic function, leading to changes in symptoms (e.g. elevated IP-10 and TNF-RII induce general fatigue and insomnia, and MMP-2 is strongly associated with mental fatigue). Local RT also reduces circulating HSCs, WBCs, lymphocytes, and platelets, which in turn appear to strongly associate with cytokines/chemokines such as TGF-β1 and MMP-2. CRP = C-reactive protein; HSC = hematopoietic stem cell; WBC = white blood cell.